1. fMRI Network Analysis and Resting State Studies a. Functional brain networks associated with risk-reward conflict in alcohol dependence Alcohol dependence is associated with heightened risk tolerance and altered decision- making. This raises the question as to whether alcohol dependent patients (AD) are incapable of proper risk assessment. We investigated how healthy controls (HC) and AD engage neural networks to cope with the increased cognitive demands of risky decisions. We collected fMRI data while 34 HC and 16 AD played a game that included safe and risky trials. In safe trials, participants accrued money at no risk of a penalty. In risky trials, reward and risk simultaneously increased as participants were instructed to decide when to stop a reward accrual period. If the participant failed to stop before an undisclosed time, the trial would bust and participants would not earn the money from that trial. Independent Component Analysis was used to identify networks engaged during the anticipation and the decision execution of risky compared with safe trials. Both HC and AD demonstrated distinct network engagement for safe and risky trials at anticipation. However, at decision execution, AD exhibited severely reduced discrimination in network engagement between safe and risky trials. Although AD behaviorally responded to risk they failed to appropriately modify network engagement as the decision continued, leading AD to assume similar network engagement regardless of risk prospects. This may reflect disorganized network switching and a facile response strategy uniformly adopted by AD across risk conditions. We propose that aberrant salience network (SN) engagement in AD might contribute to ineffective network switching and that the role of the SN in risky decisions warrants further investigation (Zhu, Sundby et al., 2016). b. Resting State Connectivity and Genetic Variants In collaborations with the various NIAAA sections, we are currently investigating the modulatory effects of several genes on resting state connectivity of alcohol dependent patients in comparison to non-dependent controls. Amongst these genes are: CD38 (with Dr. Leggio)- is a glycoprotein that functions in cell adhesion, signal transduction and calcium signaling. The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism. We have analyzed seed-based resting state functional connectivity in healthy control individuals with the minor and major allele of the CD38 gene rs3796863. Individuals with the minor allele showed increased functional connectivity between the left ventral striatum and the anterior cingulate cortex compared to individuals with the major allele. These results are being combined with other imaging (PET) and non-imaging behavioral data to investigate this genes effect on reward processing in healthy individuals. DAT1 (with Dr. Lohoff)- Altered dopaminergic signaling pathways and heightened ventral striatum (VS) activation in response to reward in addiction has been related to functional polymorphisms of the dopamine system. Dopamine related post-synaptic activity depends on the presence of dopamine in the synapse, which in turn is related to the activity of the dopamine transporter (DAT). Expression of DAT is influenced by a polymorphism of the DAT gene. Despite inconsistency in the literature (van der Zwalum et al 2009; Lind et al, 2009), there is evidence that the 9-repeat is associated with decreased DAT levels. This could represent a possible neuroimaging endophenotype of higher VS-dopamine availability reflected as higher VS reactivity in individuals with the 9-repeat allele when compared to individuals with the 10-repeat allele. We are currently conducting resting state analyses to determine whether healthy controls with the 9-repeat allele had higher VS-connectivity compared to those with the 10-repeat allele. We are also investigating if there are differences in VS-connectivity in alcohol dependent individuals with the 10-repeat allele compared to healthy control individuals. CRHNA5 (with Dr. Ramchandani)- The nictotinic acetylcholine receptor (nAChR) has been shown to be associated with nicotine addiction, and potentially alcohol use disorders. Through a collaboration with Dr. Ramchandanis section, we will be assessing whether altered functional connectivity related to CHRNA5 mediates the risk for excessive alcohol use. 2. Structural Connectivity a. Diffusion Tensor Imaging Over the past year, CNIRC has also continued our investigation of the structural underpinnings, including structural connectivity, associated with alcohol dependence. We have examined the contribution of structural connectivity and the potential damage to white matter integrity in alcohol use disorders using MR diffusion tenor imaging in 55 alcohol dependent patients and 58 healthy controls. In this study we utilized Tract-Based Spatial Statistics and Connectometry. When comparing alcohol dependent patients with healthy controls we found interruptions in white matter massages to supramarginal and inferior parietal gyri, which are areas related to decision-making, language processing, and lack of empathy towards others; in the superior temporal gyrus which is implicated in perception of emotional and facial stimuli and more importantly social cognition processes and in pathway to amygdala; as well as compromised fiber tracts, mostly on the left side of the brain, in passages to several regions including tracts to inferior frontal gyrus, which is known to be involved in behavioral inhibition and risk aversion (manuscript in preparation).